Metformin, glyburide, and a combination of both were effective in non-insulin-dependent diabetes mellitus
ACP J Club. 1995 Mar-April;122:39. doi:10.7326/ACPJC-1995-122-2-039
Hermann LS, Scherstén B, Bitzén PO, et al. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care. 1994 Oct;17:1100-9.
To compare the effectiveness and safety of metformin and sulfonylurea, alone and in combination, in patients with non-insulin-dependent diabetes mellitus (NIDDM).
Randomized, double-blind, placebo-controlled trial with 6-month follow-up after complete dose titration.
5 primary health care centers in Sweden.
144 patients (mean age, 60 y; 63% men) with an elevated fasting blood glucose (FBG) concentration ≥ 6.7 mmol/L on ≥ 2 separate occasions or an abnormal glucose tolerance test. Exclusion criteria were conditions requiring insulin treatment or a contraindication to the study drugs.
After 6 weeks of dietary treatment and a 2-week run-in period of diet plus placebo, patients were allocated to a combination of metformin plus glyburide (n = 72), metformin alone (n = 38), or glyburide alone (n = 34). Dose titration was done every 2 weeks if FBG was ≥ 6.7 mmol/L, using, at most, 6 dose levels. For combination therapy, these levels comprised increasing doses of both medications. For single-drug therapy, the dose was increased to the maximum by the third level, and then the other study drug was added at increasing doses for the next 3 levels. Placebo tablets were dispensed to keep the number of tablets the same in all treatment groups.
Main Outcome Measures
Glycemic control, fasting and meal-stimulated C-peptide and insulin levels, body weight, blood pressure (BP), lipid levels, and adverse effects.
Single-drug therapy was insufficient in 36% and low-dose combination therapy was insufficient in 25%. Overall, the mean FBG decreased from 10.3 to 7.7 mmol/L (P = 0.001 for all groups). For patients maintained on single-drug therapy or the low-dose combination, the mean FBG decreased from 9.1 to 7.0 mmol/L (P = 0.001), with no difference between treatment groups. For patients maintained on high-dose combinations, FBG decreased from 13.3 to 7.8 mmol/L (P = 0.001), with no difference between these groups. Meal-stimulated C-peptide and insulin levels increased with glyburide therapy alone and the low-dose combination but not with metformin alone. Body weight increased with glyburide alone but remained unchanged in the other treatment groups. Patients receiving metformin had more digestive complaints than did those in the other treatment groups (P = 0.011) but had fewer central nervous system symptoms (P = 0.036).
Metformin and glyburide achieved similar glycemic control in patients with non-insulin-dependent diabetes mellitus. Digestive complaints increased with metformin but body weight and hyperinsulinemia did not. Combinations of metformin and glyburide were effective when single-agent therapy failed.
Sources of funding: Lipha Pharmaceuticals (United Kingdom) and Meda AB (Sweden).
For article reprint: Dr. L.S. Hermann, Kulperod 2958, 442 95 Kungálv, Sweden. FAX 46-303-225-769.
Sulfonylureas are used as the next therapeutic step in patients with NIDDM when diet alone does not achieve adequate glycemic control. Outside the United States, metformin (a biguanide related to phenformin) is also used for this purpose. Hermann and colleagues compared metformin and glyburide in a group of patients, most of whom had early or mild NIDDM. Each drug alone produced satisfactory glycemic control in two thirds of patients, whereas a combination of both drugs in low doses achieved control in a few more. In patients not controlled by a single drug, addition of the other agent lowered plasma glucose levels.
When 2 drugs are similarly effective, the choice between them is determined by adverse effects and cost. Biguanides produce gastrointestinal side effects; in this study, half of the patients treated with metformin alone had diarrhea, one fourth developed nausea, and one sixth complained of abdominal pain. The possibility that patients treated with metformin did not gain weight because of the anorectic effect of these symptoms makes this putative "advantage" of metformin less appealing. In contrast, current sulfonylureas cause few side effects other than hypoglycemia; despite conventional teaching, metformin produced this side effect, too. Although cost was not addressed, metformin is unlikely to be less expensive than generic sulfonylurea preparations.
Metformin appears useful as a second drug in patients with inadequate glycemic control taking sulfonylureas alone, but whether this combination is preferable to changing therapy to a single dose of intermediate-acting insulin remains to be seen.
The forthcoming report of the U.K. Prospective Diabetes Study (1) may provide a firmer basis for choosing drug therapy in NIDDM. Meanwhile, these results favor sulfonylureas rather than metformin as the next therapy when diet alone fails.
William E. Clutter, MD
Washington University School of Medicine St. Louis, Missouri